Inhibition of autotaxin activity ameliorates neuropathic pain derived from lumbar spinal canal stenosis

Abstract

Lumbar spinal canal stenosis (LSS) or mechanical compression of dorsal root ganglion (DRG) is one of the causes of low back pain and neuropathic pain (NP). Lysophosphatidic acid (LPA) is a potent bioactive lipid mediator that is produced mainly from lysophosphatidylcholine (LPC) via autotaxin (ATX) and is known to induce NP via LPA1 receptor signaling in mice. Recently, we demonstrated that LPC and LPA were higher in cerebrospinal fluid (CSF) of patients with LSS. Based on the possible potential efficacy of the ATX inhibitor for NP treatment, we used an NP model with compression of DRG (CD model) and investigated LPA dynamics and whether ATX inhibition could ameliorate NP symptoms, using an orally available ATX inhibitor (ONO-8430506) at a dose of 30 mg/kg. In CD model, we observed increased LPC and LPA levels in CSF, and decreased threshold of the pain which were ameliorated by oral administration of the ATX inhibitor with decreased microglia and astrocyte populations at the site of the spinal dorsal horn projecting from injured DRG. These results suggested possible efficacy of ATX inhibitor for the treatment of NP caused by spinal nerve root compression and involvement of the ATX-LPA axis in the mechanism of NP induction.

Discovery of Potent Selective Nonzinc Binding Autotaxin Inhibitor BIO-32546

“…Encouraged by the evidence that ATX and LPA levels are increased upon neuronal injury and that production of LPA up-regulates pain-related proteins through the LPA1 receptor, we were particularly interested in developing an ATX inhibitor for neuropathic pain. Very recently, it was reported that an ATX inhibitor ONO-8430506 could ameliorate neuropathic pain symptom in CD rat model at 30 mg/kg, , which further strengthens this hypothesis. Our initial screening of an internal lipid mimetic chemical library derived from our previous S1P work and subsequent optimization identified a hit compound 5 (Figure ), a phosphonic acid-based inhibitor that inhibits ATX in the FRET assay with good potency (IC 50 = 28 nM).…”

Lysophosphatidic Acid Induced Apoptosis, DNA Damage, and Oxidative Stress in Spinal Cord Neurons by Upregulating LPA4/LPA6 Receptors

“…Beta-actin were used as [15]. LPA, a potent bioactive lipid mediator, is mainly produced from lysophosphatidylcholine (LPC) via autotaxin (ATX) [1]. Therefore, we examined the expression of LPA, LPC, and ATX in CSF of different patients.…”

“…Lumbar spinal stenosis (LSS) is a common spinal degenerative clinical disease and one of the clinical manifestations of neuropathic pain [ 1 ]. Most symptoms of LSS are attributed to compression of the spinal cord, nerve roots, or cauda equina [ 2 ].…”

“…In neural mechanisms, LPA produced by autotaxin (ATX) affects the central nervous system (CNS) by regulating neural progenitor physiology, neuronal cell death, axon retraction, and inflammation, further causing neurological damage and neuropathic pain [ 9 ]. Recent studies have found that the level of LPA in the CSF of LSS patients was significantly increased [ 1 ]. Meanwhile, another study found that LPA promoted apoptosis of spinal cord neurons and mediated LSS injury [ 10 ].…”

Lysophosphatidylcholine: Potential Target for the Treatment of Chronic Pain

“…Intrathecal LPC-induced mechanical allodynia and thermal hyperalgesia were significantly reduced in autotaxin heterozygous animals, indicating reduced conversion of LPC to LPA [ 104 ]. Moreover, ATX inhibition could ameliorate neuropathic pain symptoms by using ATX inhibitor (ONO-8430506) [ 109 ]. In addition, a recent study demonstrated that nerve injuries induced the production of LPA by converting LPC to LPA under the action of ATX, which was observed only in the spinal dorsal horn, but not in the spinal nerve, sciatic nerve, or DRG, for several hours.…”